The avermectins and the structurally related milbemycins are groups of naturally occurring macrocyclic spiro-ketal lactones that are notable as extremely potent parasiticidal agents. On account of their outstanding activity and low mammalian toxicity these compounds are extremely useful in controlling nematode and arthropod mediated disease states. The applicant will study the total synthesis of four avermectins Alb, Blb, A2b and B2b. In addition a series of simplified analogs bearing substitution changes in the spiro-ketal entity will be assembled. This study should lead to the development of generally useful synthetic methodology including the preparation of spiro-ketals directly from delta-lactones, the elaboration of the crucial hexahydrobenzofuran entity using vinyl anion methodology, the use of an epoxide and lithiomethyldiphenylphospine oxide condensation reaction and a Mitsunobu ring closure. The methods will be adapted to prepare calyculin A which is a marine spiro-ketal antitumoral. This natural product contains the 1,7-dioxaspiro(5.4)decane skeleton. Specifically the applicant will seek to employ novel rearrangement reactions to prepare this key spirane system from a spirodihydropyrone. In addition the studies should lead to the introduction of a novel mild oxazole synthesis based upon nitroalkene intermediates, a variation of the Shapiro reaction for the preparation of acetylenes, and a hydrazine based strategy for the stereospecific elaboration of the calyculin amino-amide unit. This investigation should lead to the preparation of diverse compounds for biological evaluation and thereby the design of better clinically useful compounds. in addition a series of novel generally useful synthetic organic methodologies will be developed.